Effects of Menthol on α3β4∗ Nicotinic Receptors

Abstract

Manufacturers add menthol to roughly 30% of tobacco cigarettes sold in the US, and to an unknown fraction of other tobacco products and electronic cigarettes. Smokers of menthol cigarettes find it harder to quit smoking, raising questions about the mechanism of this apparently harmful menthol effect. Menthol modestly affects the pharmacokinetics of nicotine and acts as a chemical chaperone for nicotinic acetylcholine receptors (nAChRs) [1]. In this study, we have investigated the effects of menthol on α3β4∗ nAChRs, which are mostly expressed in medial habenula (MHb) - interpeduncular nucleus (IPN) circuit: a key mediator of nicotine's aversive properties and withdrawal [2]. Fluorescently labeled α3 and β4 subunits are transiently expressed in Neuro-2a cells to form monomers, and oligomers. Using a Förster Resonance Energy Transfer (FRET) micro-spectroscopy method [3], we have found that menthol up-regulates α3 subunit while having no effects on β4 subunit and α3β4 pentamer numbers. Our results also show that menthol favors (α3)3(β4)2 stoichiometry over (α3)2(β4)3 stoichiometry. However, the study using Total Internal Reflection Fluorescence Microscopy (TIRFM) reveals that though menthol up-regulates α3 subunit numbers in peripheral Endoplasmic Reticulum, it decreases the α3β4 receptor numbers at the plasma membrane.

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